6-aryl-5-ethyl-pyrimidin-4-ol compounds useful as intermediates and bronchodilators

ABSTRACT

4-Hydroxy-5-ethyl-6-arylpyrimidines are useful intermediates leading to the synthesis of 4-amino-5-ethyl-6-arylpyrimidines, inhibitors of platelet aggregation and bronchodilators. 4Hydroxy-5-ethyl-6-phenylpyrimidine is also useful as a bronchodilator.

United States Patent [191 DeAngelis et a1.

[11] 3,890,321 [451 June 17, 1975 6-ARYL-5-ETHYL-PYRlMlD1N-4-OLCOMPOUNDS USEFUL AS INTERMEDIATES AND BRONCHODILATORS [75] Inventors:Gerald George DeAngelis, Wilton;

Hans-Jurgen Ernst Hess, Old Lyme,

both of Conn.

[73] Assignee: Pfizer Inc., New York, NY.

[22] Filed: June 19, 1973 [21] Appl. No.: 371,563

Related US. Application Data [60] Division of Ser. No. 182,220, Sept.20, 1971, which is a continuation-in-part of Ser. No. 78,216, Oct. 5,1970, Pat. No. 3,707,560.

[52] US. Cl. 260/251 R; 260/2564 C; 260/2565 R [51'] Int. Cl C07d 51/38[58] Field of Search 260/251 R, 256.4 C, 256.5 R

[56] References Cited UNITED STATES PATENTS 3,047,462 7/1962 Maillard eta1. 167/65 OTHER PUBLICATlONS Robba, et al., C.A.55,5512h (1961) PrimaryExaminer-Donald G. Daus Assistant Examiner-Raymond V. Rush Attorney,Agent, or FirmCorino1ly and Hutz 2 Claims, N0 Drawings6-ARYL-5-ETHYL-PYRIMIDIN-4-OL COMPOUNDS USEFUL AS INTERMEDIATES ANDBRONCHODILATORS CROSS REFERENCE TO RELATED APPLICATIONS This applicationis a division of copending application Ser. No. 182,220 filed Sept. 20,1971 which is a continuation-in-part of application Ser. No. 78,216filed Oct. 5, 1970 and which issued to U.S. Pat. No. 3,707,560 Dec. 26,1972.

BACKGROUND OF THE INVENTION This invention relates to 6-arylpyrimidines,and more particularly to a series of 4-substituted amino derivatives andsalts thereof and to the use of said agents as inhibitors of plateletaggregation and bronchodilators in mammals, and to a series ofcorresponding 4- hydroxy derivatives, useful as intermediates. Theinvention is further concerned with 4-hydroxy-5-ethyl-6-phenylpyrimidine and its use as a bronchodilator.

The synthesis of 4-amino-6-phenylpyrimidine has been reported byBredereck, et al., Chem. Ber., 90, 942 (1957) and by van der Plas, etal., Tetrahedron Lett., N0. 31, 2093 (1964), with no disclosure ofutility. The preparation, also without mention of use, of 4-amino-6-(p-t-butylphenyl)pyrimidine was reported by van der Plas, Rec. Trav.Chim., 84, 1101 (1965).

Khromov-Borisov, Dokl. Akad. Nauk. USSR, 180, 11129 (1968) has reportedproperties of 4-amino-6- methylpyrimidine with no utility disclosure.

SUMMARY OF THE INVENTION The inhibitors of platelet aggregation of thisinvention are represented by the formula:

Ar W R L901; 3 I.

and the acid addition salts thereof, wherein:

Air is selected from the group consisting of phenyl; monosubstitutedphenyl wherein said substituent is methyl, methoxy, 3,4-dimethoxy,hydroxy, triluormethyl, fluorine, chlorine, bromine, carboxy, cyano,nitro, dialkylamino said alkyl containing from 1 to 3 carbon atoms,amino or acylamino containing from 1 to 4 carbon atoms; pyridyl;thienyl; furyl; monosubstituted pyridyl, thienyl or furyl wherein saidsubstituent is acylamino containing from 1 to 4 carbon atoms; naphthyl;3-indolyl; 2- and 3-benzothienyl; and 2- and 3-benzofuryl;

R, and R are each selected from the group consisting of hydrogen; alkylcontaining from 1 to 4 carbon atoms; substituted ethyl wherein saidsubstituent is selected from the group consisting of 2-dimethylamino,Z-hydroxy and 2,2,2-trifluoro; alkenyl containing from 3 to 4 carbonatoms; pyridylmethyl; 2-monosubstituted phenyl wherein said substituentis carboxy orsulfamoyl; and cycloalkyl containing from 3 to 7 carbonatoms;

R and R when taken together with the nitrogen atom to which they areattached form a heterocyclic ring of the formula:

wherein Z is selected from the group consisting of CH 0, S and N-alkylcontaining from 1 to 3 carbon atoms; and n and m are integers of from 2to 3; and

R is selected from the group consisting of hydrogen and alkyl containingfrom I to 3 carbon atoms.

Of particular interest, because of their potency for inhibition ofplatelet aggregation, are compounds wherein R and R are each hydrogen,alkyl up to 4 carbon atoms and substituted ethyl where said substituentis 2-hydroxy or 2,2,2-trifluoro, Ar is phenyl or monosubstituted phenyland R is hydrogen or alkyl containing from I to 3 carbon atoms.

In addition to their activity as inhibitors of platelet aggregationseveral compounds of the instant invention are potent relaxants ofsmooth muscle and in particular bronchial tissue. Of particular interestas bronchodilators are congeners where R, and R are alkyl of up to 4carbon atoms, Ar is acylamino-substituted phenyl or naphthyl and R ishydrogen or alkyl containing from I to 3 carbon atoms.

Also part of the present invention are a series of4-hydroxy-6-arylpyrimidines of the formula:

wherein:

R is selected from the group consisting of hydrogen and alkyl containingfrom I to 3 carbon atoms; and

Ar is selected from the group consisting of phenyl provided that when Aris phenyl, R is ethyl; substituted phenyl wherein said substituent ismethyl, methoxy, 3,4-dimethoxy, hydroxy, trifloromethyl, fluorine,chlorine, bromine, carboxy, cyano, nitro, dialkylamino said alkylcontaining from I to 3 carbon atoms, amino or acylamino containing from1 to 4 carbon atoms; pyridyl; thienyl; furyl; monosubstituted pyridyl,thienyl or furyl wherein said substituent is acylamino containing from 1to 4 carbon atoms; naphthyl; 3-indolyl; 2- and 3- benzothienyl; and 2-and 3-benzofuryl.

In addition to their utility as intermediates leading to thecorresponding 4-amino-6-arylpyrimidines, one of the above-mentioned4-hydroxypyrimidines, namely, 4-hydroxy-5-ethyl-6-phenylpyrimidine,possesses unexpected activity as a relaxant of smooth muscle and inparticular, bronchial tissue.

DETAILED DESCRIPTION OF THE INVENTION In accordance with the processemployed for the preparation of compounds of the instant invention,several alternate synthetic methods are used. The first synthetic route,Method A, is illustrated by the following scheme:

CN I NH Ar-MgX R -lcn 2 3 C-OC l'l 2 2 5 l 2 5 Ar N 1 HCOMl 3 0 11 POClAr R C) :l

III

Ar N 111 R R MI O R N In the first reaction step of the aforementionedpentachloride converts the 4-hydroxy-6- scheme, an aryl Grignard iscontacted with an ester of cyanoacetate in a reaction inert solvent. Inpractice, the aryl Grignard, generated in situ from the aryl halide andmagnesium turnings in a solvent such as ether, is treated with an esterof cyanoacetate, generally the methyl or ethyl ester, in the samesolvent. It is desirable to use at least a 200% excess of the requisitieGrignard reagent to effect a maximum yield of product.

The aforedescribed reaction is carried out at ambient temperatures forseveral hours followed by subsequent hydrolysis of the reaction mixturewith dilute sulfuric acid and extraction of the amino ester into theether phase. Removal of the solvent is followed by purification bydistillation if the product (I) is an oil or recrystallization when asolid.

Alternately, an aryl lithium salt can be used in place of the Grignardreagent without markedly affecting the course of the reaction.

The requisite Grignard reagents are available commercially or can besynthesized from the corresponding aryl halide, which are commercialproducts, by methods available to those skilled in the art, e.g., asoutlined by Kharasch, et al., Grignard Reactions of NonmetallicSubstances, Prentice-Hall, New York, 1954.

Cyclization of the B-amino arylacrylic esters (l) to the4-hydroxy-o-arylpyrimidines (II) is carried out in a highly polar,reaction-inert solvent such as dimethylsulfoxide or dimethylformamideemploying a five to ten fold excess of formamide and at least twoequivalents of an alkali metal lower alkoxide such as potassiumtbutoxide or sodium ethoxide. Temperatures of from 75l00 C. are employedwith reaction times of 5-24 hours. Isolation of the desired product iscarried out by pouring the reaction mixture onto ice followed byacidification with glacial acetic acid. Further purification is effectedby recrystallization from a suitable solvent.

The action of halogenating agents such as thionyl chloride, phosphorousoxychloride or phosphorous arylpyrimidines (II) to the 4-chloro analog(Ill). Experimentally, II is added to a large excess of the chlorinatingreagent, preferably phosphorous oxychloride, and the mixture heated toreflux from I to 2 hours. Lower temperatures can be employed withcorrespondingly longer reaction times. After removal of excess reagentin vacuo, the residual product is poured into a mixture of ammoniumhydroxide and ice. The crude product can be used in the next reaction ormay be further purified via recrystallization.

Displacement of the 4-chloro substituent of compounds of formula III,leading to the products of the present invention, is carried out in areactioninert solvent, e.g., ethanol or tetrahydrofuran with ammonia oran amine, HNR R wherein R and R are as previously described.Alternately, the reaction can be carried out neat, i.e., withoutsolvent. In practice, at least 2 moles of ammonia or amino per mole ofIII is employed, and as much as a 10 fold excess can be employed. It isgenerally advantageous to heat the aforementioned reaction from about50l00 C for periods of 28 hours. Work-up of the reaction constitutespouring the mixture into water followed by extraction of IV into anonaqueous solvent such as chloroform and subsequent conversion of thefree base to a suitable salt, e.g., hydrochloride, by treating asolution of said base with the appropriate acid.

Also within the scope of this invention are compounds of formula IVwherein a methyl or ethyl substituent exists at the 2-position.Introduction of the methyl or ethyl substituent into the 2-positionrequires the use of acetamide or propionamide in place of formamide inthe second step of the described sequence. In general, the substitutionof the aforementioned starting materials does not markedly affect thecourse or yields of the reactions involved.

Method A is particularly applicable to the preparation of compounds offormula IV wherein R R and R are as previously described and where Ar ispyridyl, thienyl, fury], naphthyl, 3-indolyl, 2- and 3-benzothienyl, 2-and 3-benzofuryl, phenyl and monosubstituted phenyl where saidsubstituents are methyl, methoxy, 3,4- dimethoxy, trifluoromethyl,fluorine, chlorine and bromine.

Also within the purview of this invention are congeners of IV wherein Arincludes 3,4- methylenedioxyphenyl, acetylphenyl and disubstitutedphenyl where the second substituent is selected from the groupconsisting of methyl, methoxy, fluorine, chlorine, bromine and ethoxy.

The first alternate series of reactions, Method B, leading to theproducts of the present invention, is outlined as follows:

a 9.861%, CD a,

In the first reaction of the aforementioned Method B an appropriatelysubstituted o-chlorobenzonitrile is contacted with a salt of a loweralkyl thioglycolate ester in a reaction-inert solvent. In practice,sodium methyl thioglycolate, prepared by treating methyl thioglycolatewith an equivalent amount of sodium alkoxide in a lower alkanol solventfollowed by removal of the solvent in vacuo, is added to areaction-inert solvent, preferably of moderately high polarity, e.g.,dimethylformamide or hexamethylphosphoramide. The resulting solution orsuspension of sodium methyl thioglycolate is treated with an equimolaramount of the requisite ochlorobenzonitrile dissolved in the samesolvent.

Alternately, the sodium salt of the methyl thioglycolic acid can begenerated in situ in said reaction employing either an equimolar amountof sodium hydride or a sodium alkoxide.

The aforedescribed reaction is carried out at 50l00 C. for a period of15 minutes to 2 hours. A convenient method of isolation is to cool thereaction mixture and subsequently add it to a mixture of ice and water.The desired solvent can be filtered, dried, and recrystallized from asuitable solvent.

The requisite o-chlorobenzonitriles are available commercially or can besynthesized by one skilled in the art, e.g., by the method of Nakaoka,et al., German Pat. No. 1,230,026 (CA. 66, 55255e).

Cyclization of the 2 -carbomethoxy-3-aminobenzothiophenes (V) to thetricyclic 4hydroxybenzothieno[3,2-d]pyrimidines (V1) is carried out in areaction-inert solvent such as dimethylsulfoxide or dimethylformamideusing a 5 to fold excess of formamide and an equimolar amount of analkali metal lower alkoxide such as sodium methoxide or potassiumtbutoxide. Reaction temperatures of 75100 C. are employed with areaction time of 30 minutes to 2 hours. The desired product is isolatedby pouring the cooled reaction mixture into water followed byacidification with acetic acid, filtration and drying. The product canbe further purified by trituration or recrystallization from a suitablesolvent.

The action of halogenating agents, e.g., thionyl chloride, phosphorousoxchloride or dichlo'rophenylphosphine oxide converts the4-hydroxybenzothieno[3,2- d]pyrimidines (VI) to the corresponding4-chloro analogs (VII). In practice, V1 is added to a large excess ofthe appropriate reagent, preferably phosphorous oxychloride, and themixture heated. Reflux temperatures are preferred, although lowertemperatures may be employed with correspondingly longer reaction times.The reaction period is not critical, but will vary with temperature,concentration and reactivity of the starting reagents. In general, aperiod of from about 2 to about 8 hours is operable. A convenient methodof isolation comprises removal of the excess phosphorous oxychloride invacuo followed by treatment of the residue with water and sufficientammonium hydroxide solution to render the solution basic. The resultingproduct is filtered and air dried. It can be used in this crude statefor subsequent reaction or can be recrystallized from an appropriatesolvent.

Displacement of the 4-chloro substituent of compounds of formula VII,leading to VIII, is effected in a reaction-inert solvent with ammonia oran amine, I-INR R wherein R and R are as previously described. Inpractice, a mixture of the appropriately substituted4-chlorobenzothieno[3,2-d]pyrimidine and ammonia or a suitable amine areheated in a solvent such as ethanol, dimethylformamide, benzene ortetrahydrofuran. It is advantageous to employ at least 2 moles of amineper mole of halide, and as much as a 10 fold excess can be employed. Itis generally desirable to ehat the aforementioned reaction mixture totemperatures from about 40150 C., with a preferred range of 75l00 C.Reaction times are not critical, and will vary with reactiontemperature, molar quantities of reactants, etc. In general, periods of1 to 6 hours are operable.

Isolation of the products following the aforedescribed reaction is mostconveniently carried out by diluting with water followed by extractionwith a water immiscible solvent, e.g., chloroform, ether or benzene. Theseparated, non-aqueous phase is then dried over a suitable drying agentand the solvent removed in vacuo.

The final reaction of Method B, leading to the produts of the presentinventon, comprises desulfurization of the4-aminobenzothieno[3,2-d]pyrimidines (VIII) using an excess of Raneynickel. Experimentally, the reaction is carried out in a highly polar,reaction-inert solvent such as dimethylformamide and at temperatures of-150 C. Reaction times are not critical, but the preferred range is from24-48 hours. Removal of the spent Raney nickel followed by concentrationof the filtrate to dryness provides the crude free base of the desiredproduct, which is converted to hydrochloride salt by conventionalmethods. Products isolated by Method B prove to be identical with thosesynthesized by Method A.

The aforedescribed method is particularly useful for the preparation ofproducts of the instant invention wherein R and R are as previouslydescribed, R is hydrogen and Ar is phenyl and monoor disubstitutedphenyl where said substituent is methyl, methoxy, 3,4- dimethoxy, cyanoor carboxy.

The third alternate approach to the synthesis of compounds of thepresent invention (Method C) is outlined in the following scheme:

0 5 Ar SH Ar-CCi-IC-UC ll (x5 C5 v 2 5 2 2 R3/\/ on IX Ranev )(ickel Qt-3 H POCl Ar W III In HAR R Ar X N R R2 The initial step in the reactionsequence of Method C is a condensation of a (lower)alkyl aroylacetatewith thiourea resulting in the formation of a 4-hydroxy-2-mercapto-6-arylpyrimidine (IX). In practice, the requisite B-ketoesteris contacted with approximately equimolar amounts of thiourea in areaction-inert solvent such as those represented by the (lower)alkanols.Temperatures of 6090 C. are operable with corresponding reation times ofabout 96-140 hours. Isolation of the desired product is achieved byconcentration of the reaction mixture in vacuo followed by dilution withwater, acidification to pH 3, cooling and, finally, filtration of thecrude solids.

Alternately, S-methylisothiourea may also be employed in place of ureain the above described reaction and provides the corresponding2-methylthio analog of IX.

The aroylacetates are either commercial products or can be convenientlysynthesized by methods available to those skilled in the art, e.g.,according to those extensively outlined by Hauser, et al., in OrganicReactions, John Wiley and Sons, Inc., New York, 1954, Chapter 9, page266. Aroyl-a-substituted -acetates, Ar- COCl-l(R;,)CO C l-l aresynthesized according to the procedure as taught by Hope, et al., J.Chem. Soc., 95, 2045 (1909).

Desulfurization of IX in aqueous sodium hydroxide using Raney nickelresults in the formation of the cor responding4-hydroxy-6-arylpyrimidine (ll), identical to that prepared by Method A.Similarly, when the corresponding S-methyl analog of IV is employed,identical products are obtained.

The subsequent steps of the reaction sequence, Method C, andcorresponding results are identical to those of Method A.

Method C is especially useful for the preparation of compounds of theinstant invention where R,, R and R are as indicated previously andwhere Ar is phenyl or monoor disubstituted phenyl said substituentsbeing cyano, methyl, methoxy, carboxy, acylamino or dialkylamino,pyridyl, furyl and acylamino substituted pyridyl and furyl, 3-indolyl,naphthyl and 2- and 3- benzofuryl.

Further, the use of an a-alkylaroylacetate in the initial reaction ofMethod C allows the synthesis of 5-alkyl congeners of the final products(IV). Substitution of acetamidine or propionamidine for thiourea leadsto analogs of IV bearing a Z-methyl or 2-ethyl substituent.

introduction of a nitro substituent into the aryl moiety of the4-amino-6-arylpyrimidines can be carried out by direct nitrationemploying a mixture of nitric and sulfuric acids. In practice, to asolution of the substrate in concentrated sulfuric acid is added,dropwise and at room temperature, nitric acid. The resulting reaction iscarried out at ambient temperatures for about 2-6 hours. The reaction isquenched with ice, made basic with ammonium hydroxide and the free baseextracted into a water immiscible solvent such as chloroform ormethylene chloride.

in general, more than one nitroisomer is formed as a result of directnitration. These isomers can subsequently be separated by conventionalmethods known to those skilled in the art, e.g., by fractionalcrystallization or column chromatography. Identification of said isomersis most conveniently carried out using nuclear magnetic resonancestudies.

Treatment of the aforedescribed nitro compounds with reducing agents,such as stannous chloride and hyrochloric acid, results in thepreparation of the corresponding amino analogs. Stannous chloridereductions are carried out at temperatures of 4075 C. with reactiontimes of 2 to 4 hours, and preferably employ l2N hydrochloric acid. Theproduct, which is frequently sparingly soluble as the dihydrochloridesalt in 12N hydrochloric acid, is filtered from the cooled reactionmixture and the free base liberated by treatment of the salt with anaqueous base such as sodium hydroxide solution.

In addition to the aforementioned method of reducing nitro substituents,several other reducing reagents, known to those skilled in the art, canbe employed with comparable results, e.g., tin-hydrochloric acid,hydrogen-platinum oxide, or aluminum amalgam.

4-Amino-6-aminoarylpyrimidines, resulting from the above-mentionedreduction of the corresponding nitro compounds, can subsequently bereacted with a wide variety of reagents, including alkanoyl halides,anhydrides, alkyl halides, sulfonyl halides, isocyanates andthioisocyanates.

Reaction of said amino compounds with alkanoyl halides andalkoxycarbonyl halides leads to the preparation of the correspondingacylamino and alkyl carbamates, respectively. In practice, the alkanoylor alkoxycarbonyl halide is added dropwise to a mixture of theappropriate amino compound and an alkali metal carbonate in a suitablereaction-inert solvent such as benzene, ether or methylene chloride. Thereaction is preferably carried out at ambient temperatures for areaction period of about 12 to 24 hours. Hydrolysis of the reaction withwater and separation of the water immiscible solvent leads to thesubsequent isolation of the crude product.

Analogously, sulfonyl halides are reacted under simi lar conditions andgive rise to the corresponding sulfonamides.

Formation of acylamino substituents employing simple anhydrides or mixedanhydrides in place of aroyl or alkanoyl halides can be carried outwithequal ease. Experimentally, the amino compound is contacted with atleast an equimolar amount of the requisite anhydride and preferably a20-50% excess. A solvent, such as benzene, pyridyne, chloroform ortetrahydrofuran, can be employed, or the reaction can be run neat, i.e.,without solvent. in the latter case it is desirable to use as much as aIOU-300% excess of the appropriate anhydride. Said reaction is carriedout for 12 to 24 hours at ambient temperatures. The excess anhydride canbe removed under reduced pressure and the residue dissolved in ethylacetate after which it is converted to the desired salt or alternately,the original reaction mixture can be diluted with ethyl acetate and thesalt prepared directly by conventional methods.

Reaction of 4-amino-6-aminoarylpyrimidines with isocyanates andisothiocyanates gives rise to the corresponding ureas and thioureas.Said reactions are effected with the appropriate amino substrate and anequimolar amount, plus as much as a 20% excess, of the requisiteisocyanate or thioisocyanate in a reactioninert solvent, e.g., ether,,tetrahydrofuran or benzene. Reaction times of about 12 to 24 hours atroom temperature are generally adequate. Isolation of the desiredproduct is achieved by removal of the solvent under reduced pressurefollowed by recrystallization of the residue from a suitable solvent.

Synthesis of 6-(N-alkylaminoaryl)pyrimidines and6-(N,N-dialkylaminoaryl)pyrimidines is conveniently carried out bydirect alkylation of the 6- aminoarylpyrimidines using an appropriatealkyl halide. The extent of alkylation is controlled by the relativeamount of alkyl halide, generally the iodide, to the amino compoundemployed. For monoalkylation equimolar quantities of the two reactantsare used pluse a small, 10% excess of the alkyl halide; dialkylationrequires at least two moles of halide per mole of amino substrate.Allylic halides aralkyl halides can also be used with similar ease.

in practice, a solution or suspension of the aminoarylpyrimidine and atleast an equimolar amount of an alkali metal carbonate is treated withthe appropriate alkyl halide, preferably the iodide, in the amountspreviously described. The solvents for this alkylation can vary innature and are selected from the group including (lower)alkanols,N,N-di(lower)alkyl(lower)alkylcarboxamides, cyclic ethers and water.Elevated temperatures of from 50-1 C. are employed, with reaction timesof 1-8 hours. The product is isolated by evaporation of the reactionsolvent in vacuo followed by extraction of the residue with suchsolvents as meth ylene chloride or chloroform or, alternately, whenwater is used as the reaction solvent the product can be extracted fromthe mixture directly using said solvents. The separated extractingsolvent is evaporated to dryness and the crude product purified byrecrystallization from a suitable solvent or chromatographing on asilica gel column.

Also considered within the scope of the present in vention are congenerswherein R and R when considered together with the nitrogen atom to whichthey are attached form a piperazine ring of the formula where X is(lower)alkyl, (lower)alkoxy, (lower)alkyleneoxy, phenyl, furyl, thienyl,di(lower)alkylamino, l-piperidyl and ar(lower)alkyloxy.

As has been previously noted, compounds of the instant invention canform acid addition salts. Basic compounds of the present invention areconverted to the acid addition salts by interaction of the base with anacid either in an aqueous or non-aqueous medium. In a similar manner,treatment of the acid addition salts with an aqueous base solution,e.g., alkali metal hydroxides, alkali metal carbonates and alkali metalbicarbonates or with a metal cation which forms an insoluble precipitatewith the acid anion, results in a regeneration of the free base form.Such conversions are best carried out as rapidly as possible and undertemperature conditions and method dictated by the stability of saidbasic products. The bases thus regenerated may be reconverted to thesame or a different acid addition salt.

In the utilization of the chemotherapeutic activity of those compoundsof the present invention which form salts, it is preferred, of course,to use pharmaceutically acceptable salts. Although water-insolubility,high toxicity, or lack of crystalline nature may make some particularsalt species unsuitable or less desirable for use as such in a givenpharmaceutical application, the water insoluble or toxic salts can beconverted to the corresponding pharmaceutically acceptable bases bydecomposition of the salt as described above, or alternately they can beconverted to any desired pharmaceutically acceptable acid addition salt.

Examples of acids which provide pharmaceutically acceptable anions arehydrochloric, hydrobromic, hydroiodic, nitric, sulfuric, or sulfurous,phoshporous, acetic, lactic, citric, tartaric, succinic, maleic, andgluconic.

The terminal complication of thrombus formation in ischaemic heartdisease, cerebral vascular disease, legvein thrombosis, pulmonaryembolism and peripheral vascular disease is well documented in themedical literature, and has recently been reviewed by Mustard, et al.,Pharm. Rev., 22, 97 (1970). The causal role of platelet aggregation inthe formation of thrombi, which are masses of agglutinated platelets andleucocytes as distinguished from clots in which the elements of theblood are randomly distributed, has been postulated by many medicalstudies and has been reviewed by Mustard, et al. The compounds of theinstant invention mediate their remarkable antithrombogenic activitythrough their ability to inhibit the aforementioned plateletaggregation.

As previously indicated, the 4-amino-6- arylpyrimidines of the presentinvention are all readily adapted to therapeutic use as inhibitors ofplatelet aggregation. Typical member compounds of interest in thisseries include 4-diethylamino-6-(p-methoxyphenyl)pyrimidine,4-diethylamino-6- phenylpyrimidine, 4-(ethyl-n-propylamino)-6-phenylpyrimidine, 4-diethylamino-6(2- thienyl)pyrimidine,4-diethylamino-6-(m-dimethylaminophenyl)pyrimidine, 4-[ethyl(2-hydroxyethyl)amino]-6-phenylpyrimidine, 4-ethylamino-6-phenylpyrimidine, 4-(2,2,2-trifluoroethylamino)-6-phenylpyrimidine, 4-

diethylamino-S-methyl-6-phenylpyrimidine and 4-diethylamino-S-ethyl-6-phenylpyrimidine.

In addition to their usefulness as inhibitors of platelet aggregation,several congeners of this series show outstanding potency as smoothmuscle relaxants and in particular as bronchodilators. Compounds notablefor this therapeutic usefulness include 4-diethylamino-6-(m-acetylaminophenyl)pyrimidine, 4-diethylamino-6-(m-isobutrylaminophenyl)pyrimidine, 4-diethylamino-6-(m-propionylaminophenyl)pyrimidine,4-di-npropylamino-6-(m-acetylaminophenyl )-pyrimidine and4-diethylamino-6-(p-acetylaminophenyl)pyrimidine.

The 4-hydroxy-6-arylpyrimidines of the present invention, as previouslymentioned, are useful intermediates leading to the synthesis of thecorresponding 4-amino-6-arylpyrimidines. In addition, it has been foundthat at least one of these intermediates, 4-hydroxy-S-ethyl-6-phenylpyrimidine, has unexpected, outstanding activityas a bronchodilator. It is especially interesting, since thecorresponding analogs wherein R is hydrogen, methyl and propyl haveconsiderably less activity.

The 4-amino-6-arylpyrimidines and 4-hydroxy-5- ethyl-6-phenylpyrimidineand the pharmaceutically acceptable salts thereof, which are useful asinhibitors of platelet aggregation and/or bronchodilators in mammals,may be administered either as individual therapeutic agents or asmixtures of therapeutic agents. They may be administered alone, but aregenerally administered with a pharmaceutical carrier selected on thebasis of the chosen route of administration and standard pharmaceuticalpractice. For example, they may be combined with variouspharmaceutically acceptable inert carriers in the form of tablets,capsules, lozenges, troches, hard candies, powders, sprays, aqueoussuspensions or solutions, injectable solutions, elixirs, syrups and thelike. Such carriers include solid diluents, or filters, sterile aqueousmedia and various nontoxic organic solvents. Moreover, the oralpharmaceutical compositions of this invention may be suitably sweetenedand flavored by means of various agents of the type commonly used forthis purpose.

The particular carrier selected by the proportion of active ingredientto the carrier are influenced by the solubility and chemical nature ofthe therapeutic compounds, the chosen route of administration and theneeds of the standard pharmaceutical practice. For example, where thosecompounds are administered orally in tablet form, excipients such aslactose, sodium citrate, calcium carbonate and dicalcium phosphate maybe used. Various disintegrants such as starch, alginic acids, andcertain complex silicates together with lubricating agents such asmagnesium stearate, sodium lauryl sulphate and talc, may also be used inproducing tablets for the oral administration of these compounds. Fororal administration in capsule form, lactose and high molecular weightpolyethylene glycols are among the preferred materials for use aspharmaceutically acceptable carriers. Where aqueous suspensions are tobe used for oral administration, the compounds of this invention may becombined with emulsifying or suspending agents. Diluents such asethanol, propylene glycol, glycerine and their combinations may beemployed as well as other materials.

For purposes of parenteral administration and inhalation, solutions orsuspensions of the instant compounds in sesame or peanut oil or inaqueous propylene glycol solutions can be employed, as well as sterileaqueous solutions of the soluble acid addition salts describedhereinafter. These particular solutions areespecially suited forintramuscular and subcutaneous injection purposes. The aqueoussolutions, including those of the acid addition salts dissolved in puredistilled water, are also useful for intravenous injection purposesprovided that their pH is properly adjusted beforehand. Such solutionsshould also be suitably buffered, if necessary, and the liquid diluentfirst rendered isotonic with sufficient saline or glucose.

The compounds may be administered to subjects suffering frombronchoconstriction by means of inhalators or other devices which permitthe active compounds to come into direct contact with the constrictedareas of the tissues of the subject. When administered by means of aspray formulated as a 1% solution, utilization several times a day ispreferred.

It is necessary that the active ingredient form a proportion of thecomposition such that a suitable dosage form will be obtained.Obviously, several dosage unit forms may be administered at about thesame time. Although compositions with less than 0.005% by weight ofactive ingredient might be used in certain instances, it is preferred touse compositions containing not less than 0.005% of the activeingredient; otherwise the amount of carrier becomes excessively large.Activity increases with the concentration of the active ingredient. Thecomposition may contain 10, 50, 75, 95 or an even higher percentage byweight of the active ingredient.

Although the use of the present invention is directed toward thetreatment of mammals in general, the preferred subject is humans. Indetermining an efficacious dose for human therapy, results of animaltesting are frequently extrapolated and a correlation is assumed betweenanimal test behavior and proposed human dosage. When a commerciallyemployed standard is available, the dose level of the clinical candidatein humans is frequently determined by comparison of its performance withthe standard in an animal test. For example, theophylline is employed asa standard bronchodilator and is administered to humans at the rate of150 to 300 mg. every 4 hours. It is assumed, then, that if compounds ofthe present invention have activity comparable to theophylline in thetest assay, that similar doses will provide comparable responses inhumans.

Obviously, the physician will ultimately determine the dosage which willbe most suitable for a particular individual, and it will vary with theage, weight and response of the particlar patient as well as with thenature and extent of the symptoms and the pharmacodynamiccharacteristics of the particular agent to be administered. Generally,small doses will be administered initially, with a gradual increase inthe dosage until the optimum level is determined. It will often be foundthat when the composition is administered orally, larger quantities ofthe active ingredient will be required to produce the same level asproduced by a small quantity administered parenterally.

Having full regard for the foregoing factors it is considered that aneffective daily dosage of the compounds of the present invention inhumans of approximately 50-750 mg. per day, with a preferred range ofabout 50-350 mg, per day in single or divided doses, or at about 1 to 7mg./kg. of body weight will effectively prevent thrombus formation inhuman subjects prone to said disorder, and alleviatebronchoconstriction. These values are illustrative, and there may, ofcourse, be individual cases where higher or lower dose ranges aremerited.

The following examples are provided solely for the purpose ofillustration and are not to be construed as limitations of thisinvention, many variations of which are possible without departing fromthe spirit or scope thereof.

EXAMPLE I 4-Diethylamino-6-phenylpyrimidine hydrochloride Method A.

A. Ethyl 2-aminocinnamate (I; Ar C H To a solution of dry ethyl ether(300 ml.) is added magnesium turnings (16.9 g.). Bromobenzene (103 g.)in ether (600 ml.) is added at a rate to maintain gentle refluxing (Aniodine crystal or a ml. of methyliodide often must be added to initiatethe reaction.). Refluxing is continued until most of the magnesium hasreacted. Ethyl cyanoacetate (30 g.) is added over a 30 minute period andthe reaction mixture allowed to stir for 3 hours at room temperatureafter which time 3.5N sulfuric acid (180 ml.) is added and the reactionallowed to stir for 30 additional minutes. The aqueous layer isextracted with diethyl ether and the organic layer washed with water anddried over sodium sulfate. Removal of the ether in vacuo followed bydistillation of the residual oil gives the desired product, b.p. about0.4 mm, l38-l42 C.

B. 4-Hydroxy-6-phenylpyrimidine (II; Ar C H R To a mixture of ethyl2-aminocinnamate (54 g.; 0.28 mole) and formamide ml.) indimethylsulfoxide (700 ml.) at 100 C. is added via a dropping funnelpotassium t-butoxide (63 g.; 0.56 mole) in 300 ml. of the same solventover a 15 minute period. The solution is stirred for 16 hours at 100 C.after which time it is cooled, poured over ice (2 l.) and acetic acidadded to complete precipitation. The solid obtained upon filtration iswashed with water, isopropyl alcohol and air dried, 30 g., m.p. 266-267C.

C. 4-Chloro-6-phenylpyrimidine (Ill; Ar C H R4-Hydroxy-6-phenylpyrimidine (2.1 g.) is added to phosphorousoxychloride (60 ml.) and refluxed for 1.5 hours. Excess phosphorousoxychloride is removed in vacuo, and the dark oil poured overconcentrated ammonium hydroxide/ice. The precipitate which forms isfiltered, washed with water and dried, 2.1 g., m.p. 95--98 C.

D. 4-Diethylamino-6-phenylpyrimidine hydrochlo- A mixture of4-chloro-6-phenylpyrimidine 10.0 g.), diethylamine (7.5 g.) and ethanol(200 ml.) is refluxed for hours. At the end of this time the reactionmixture is poured into water (800 ml.) and extracted with chloreform.The chloroform layer is dried and concentrated in vacuo to an oil whichis taken up in methanol, treated with activated charcoal, filtered andthe methanol removed in vacuo. The residual oil is taken up in diethylether and anhydrous hydrogen chloride bubbled into the solution untilprecipitation is complete. Filtration yields the hydrochloride salt(6.45 g.) which is recrystallized from ethanol/hexane to yield a tanmicrocrystalline solid, 5.0 g., m.p. 2l4-215 C.

Anal. Calcd. for C,.,H N .HCl: C, 63.7; H, 6.9; N,

15.9. Found: C, 63.6; H, 7.0; N, 15.7.

EXAMPLE ll 4-Diethylamino-6-phenylpyrimidine hydrochloride Method B.

A. Z-Carbomethoxy-3-aminobenzothiophene (V; X

To a solution of t-butyl alcohol (30 ml.) and potassium t-butoxide (1.12g.; 0.01 mole) is added via a dropping funnel methyl thioglycolate (1.06g.; 0.01 mole) in t-butyl alcohol ml.). The solution is stirred for 10minutes and then concentrated in vacuo to yield the sodium salt ofmethyl thioglycolate, which is taken up in 30 ml. of dimethylformamide.To this is added via a dropping funnel 2-chlorobenzonitrile (1.37 g.;0.01 mole) in dimethylformamide (10 ml.), and the solution is warmed to75 C. for 30 minutes. At the end of this time the solution is cooled andpoured onto 200 ml. of ice and water. The resultant precipitate isfiltered, washed with water and dried to yield a white microcrystallinesolid, 1.8 g., m.p. 105106 C.

B. 4-Hydroxybenzothieno[3,2-d]pyrimidine (VI; X

To a solution of 2-carbomethoxy-3-aminobenzothiophene (2.07 g.; 0.02mole) and potassium t-butoxide (2.24 g.; 0.02 mole) in dimethylsulfoxide(30 ml.) is added an excess of formamide (ca 5 ml./g. of 2-carbomethoxy-3-aminobenzothiophene). This is heated to 90 C. until thereaction is complete as evidenced by thin layer chromatography (-30minutes). The solution is cooled, poured into water, acidified withglacial acetic acid and the resultant solid is filtered. Washing withisopropyl alcohol and then ether yields a white solid, 1.76 g., m.p.300-301 C.

C. 4-Chlorobenzothieno[3,2-d1pyrimidine (Vll; X

A mixture of 4-hydroxybenzothieno[3,2- d]pyrimidine (20 g.; 0.1 mole) inphosphorous oxychloride (500 ml.) is refluxed with stirring for 4 hours.At the end of this time the solution is cooled and concentrated in vacuoto a brown semisolid, which is poured into 250 g. ice/250 ml. ammoniumhydroxide solution. The resultant solid is filtered and air dried toyield a beige microcrystalline solid, 19.7 g., m.p. 139-140 C.

D. 4-Diethylaminobenzothieno[3,2-d]pyrimidine hydrochloride (Vlll; X H;R R C H A mixture of 4-chlorobenzothieno[3,2-d]pyrimidine g.; 0.068mole) and an excess of diethylamine in ethanol (500 ml.) is refluxedwith stirring for 3 hours. The solution is cooled, poured into water(500 ml.) and extracted with chloroform. The chloroform extracts arewashed with water, dried over sodium sulfate and the chloroform removedin vacuo to yield a dark oily residue. This is taken up in methanol,treated with activated charcoal, filtered, and the solvent removed invacuo to yield an oily residue which is taken up in diethyl ether.Anhydrous hydrogen chloride gas is bubbled into this solution untilprecipitation ceases. Filtration yields the hydrochloride salt, 13.4 g.,m.p. 226230 C.

E. 4-Diethylamino-6-phenylpyrimidine hydrochlo- To a solution of 1.5 ml.of dimethylformamide containing4-diethylaminobenzothieno[3,2-d]pyrimidine (2.0 g.) is added a largeexcess of Raney nickel and the resulting mixture heated to reflux. Wateris allowed to distill from the reaction mixture until the temperaturereaches 150 C. where refluxing is continued with rapid stirring for 48hours. The solids are filtered and the filtrate concentrated in vacuo toan oil. The residual oil is partitioned between water and chloroform andthe organic layer separated and dried over sodium sulfate. Removal ofthe solvent under reduced pressure provides an oil which when dissolvedin ethyl ether and treated with gaseous hydrogen chloride provides 1.4g. of the hydrochloride salt of the desired product, which is identicalin every respect to that synthesized via Method A.

EXAMPLE llI 4-Diethylamino-5-ethyl-6-phenylpyrimidine HydrochlorideMethod C.

A. 2-Mercapto-4-hydroxy-6-phenylpyrimidine (V;

Ar s si 3 z s) A reaction vessel is charged with 750 ml. of dry ethanol,g. (0.36 mole) of ethyl a-benzoylbutyrate, 39.3 g. (0.72 mole) of sodiummethoxide and 49.3 g. (0.82 mole) of thiourea. The reaction mixture isheated to the reflux temperature (79 C.) and stirred at that point forhours. The resulting reaction mixture is concentrated in vacuo to a lowvolume and the thick slurry then diluted with 400 ml. of water and ice.The aqueous solution is chilled to 10 C. and then acidified to pH 3.0 bythe slow addition of concentrated hydrochloric acid. The crystallineslurry is granulated for 30 minutes at 20 C. and then filtered. The cakeis washed with warm water (60 l. at 35 C.) and then dried, 35.8 g., m.p.233236 C.

B. 4-Hydroxy-5-ethyl-6-phenylpyrimidine (11; Ar

s s; R3 z s) i To a solution of 283 ml. of water containing 11.4 g. ofsodium hydroxide and 35 g. of 2-mercapto-4-hydroxy-5-ethyl6-phenylpyrimidine, under a nitrogen atmosphere andheated to 65 C. is added 265 g. of Raney Nickel in small portions. Afterheating for 2 hours on a steam bath, an additional 80 g. of Raney Nickelis added. After an hour the desulfurization is complete and the reactionmixture is cooled. The Raney Nickel is filtered, the filtrate isconcentrated in volume in vacuo and diluted with ice and water. Theaqueous solution is acidified to pH 5.0 with concentrated hydrochloricacid and stirred for 15 minutes. The resulting precipitate is filteredand dried, 22.1 g.; m.p. 180l82 C. The analytical sample isrecrystallized from chloroform-hexane.

Anal. Calcd. forC H N O: C, 72.0; H, 6.0; N, 140.

Found: C, 71.9; H, 6.0; N, 14.0.

C. 4-Chloro-5-ethyl-6-phenylpyrimidine (111; Ar

e si 3 z s) A slurry of 21.0 g. of 4-hydroxy-5-ethyl-6- phenylpyrimidinein250 m1. of phosphorous oxychloride is stirred and heated to the refluxtemperature (105-1 C.). At 78 C. all of the solid materials aredissolved, and the solution then is stirred at 1 10 C. for 24 hours. Thesolution is concentrated in vacuo to a volume, and then carefully addedat 50 C. to a mixture of concentrated ammonium hydroxide and ice. Theprecipitate is filtered and the off-white solid is air dried, 21.5 g.,m.p. 46-47 C.

Anal. Calcd. for C H CIN C, 65.9; H, 5.1; N, 12.8.

Found: C, 65.2; H, 4.9; N, 12.6.

D. 4-Diethylamino-5-ethyl-6-phenylpyrimidine hydrochloride (IV; Ar C 11R C H An ethanol solution of 12 g. of 4-chloro-5-ethyl-6-phenylpyrimidine and 16.1 g. of diethylamine is stirred at the refluxtemperature overnight. The ethanol and excess amine are removed in vacuoto provide the residual product as a thick oil. The oil is dissolved inchloroform which is subsequently washed twice with water, dried oversodium sulfate and decolorized with charcoal. The chloroform is removedunder reduced pressure, the residual oil taken up in ethyl acetate anddry hydrogen chloride gas added until the precipitate ceases to form.The product is filtered and dried, 6.9 g., m.p. 138-139.5 C.

The analytical sample was prepared by recrystallization.

Anal. Calcd. for C H ClN C, 65.9; H, 7.6; N, 14.4.

Found: C, 66.1; H, 7.6; N, 14.4.

EXAMPLE IV The procedures of Example I are repeated, using theappropriately substituted starting materials, to provide the followingcompounds in good yields:

R R R m.p.,C. Procedure H CH H 218-220 Example 1 H C H H 190-192 Example1 H nC;,H H 172-174 Example 1 H i-C H H 165-167 Example 1 H nC H H142-145 Example 1 H i-QH, H 138-140 Example 1 H H H 207-209 Example 1 CHCH; H 250-252 Example I CH n-C H H 172-174 Example 1 C H C H H 173-175Example 1 C H n-C H, H 187-188 Example 1 n-C,-,H n-C;,H H 152-154Example I n-C H nC H H 90-91 Example 1 iC H,, i-C H H 103-104 Example 1C H C H CH 201-202.5 Example 111 1-C H t--C H CH 210-212 Example 111 CHCH C H 163-166 Example 111 i-C H iC H C H 75-78 Example 111 CH CH n--C H165-166 Example 111 C H C H nC H-, 132-134 Example 111 C H C H iC -,H-,95-975 Example 111 EXAMPLE V Following the procedures of Example 11, andstarting with the requisite benzothieno[3,2-d]pyrimidine the followingproducts are prepared in moderately good yieldsz4-(1-Pyrrolidiny1)-6-phenylpyrimidine hydrochloride, m.p. 266-268 C;

4-(1-Piperidyl)-6-phenylpyrimidine hydrochloride,

hydrochlo- EXAMPLE V1 Again, employing the procedures of Example 1, anduitlizing the appropriate starting reagents, the following congeners areprepared:

4-(2,2,2-Trifluoroethylamino)-6-pheny1pyrimidine hydrochloride, m.p.195-197 C.;

4-[Ethy1(2,2,2-trifluoroethyl)amino]-6- phenylpyrimidine hydrochloride,m.p. 208 -210 C.;

4-[2-(Diethylamino)ethylamino]-6- phenylpyrimidine hydrochloride, m.p.82 C.;

4-[Methyl(2-hydroxyethyl)amino]-6- phenylpyrimidine hydrochloride, m.p.204205 C.;

4-[Ethyl(2-hydroxyethyl)amino]-6- phenylpyrimidine hydrochloride, m.p.182-184 C.;

4-[Bis(2-hydroxyethyl)amino]-6-phenylpyrimidine hydrochloride, m.p.153-155 C.;

4-(Diallylamino)-6-phenylpyrimidine hydrochloride, m.p., 273-275 C.;

4-( 3-Pyridylmethylamino)-6-phenylpyrimidine hydrochloride, m.p. 225-226C.;

4-[Methyl(3-pyridylmethyl)amino-6- phenylpyrimidine dihydrochloride,m.p. 262-266 C.;

Ethyl N-(6pheny1-4-pyrimidinyl)anthranilate hydrochloride, m.p. -170 C.;

4-Diethylamino-5-ethy1-6-(2-naphthyl)pyrimidine hydrochloride, m.p.161-162 C.;

4-Diethylamino-5-ethyl-6-(4-tolyl)pyrimidine hydrochloride, m.p. l03-104C.

EXAMPLE V1 The procedures of Example II are repeated, starting with theappropriately substituted benzothieno[3,2- d]pyrimidine, to provide thefollowing analogs:

WW /\v RI R;

H 2-pyridylmethyl CH Z-pyridylmethyl nC;,H-, 2-pyridylmethyl H3pyridylmethyl CH 3-pyridylmethyl CH 4-pyridylmethyl H 2-sulfamoylphenylCH 2-sulfamoylphenyl n-C H,, 2-sulfamoylphenyl H 2-carboxyphenyl CH2-carboxyphenyl i-C;,H-, 2-carboxyphenyl EXAMPLE IX Follwoing theprocedures of Example I, and starting with the appropriate reagents, thefollowing compounds are synthesized:

4-Diethylamin0-6-(m-chlorophenyl)pyrimidine hydrochloride, m.p. l78l80C.;

4-Diethylamino-6-(p-chlorophenyl)pyrimidine hy-4-Di(n-propyl)amino-6-(m-trifluoromethylphenyl)- pyrimidinehydrochloride, m.p. 276278 C.

Again, following the procedures of Example I, and starting with theappropriately substituted reagents, the following analongs are preparedin moderate yields:

Repeating again the procedures of Example I or III, and employing theproper starting reagents, the following o-(p-methoxypheyl)pyrimidinehydrochlorides are synthesized:

CHO

In a similar manner are prepared 4-diethylamino-6-(3,4-diemthoxyphenyl)pyrimidine hydrochloride, m.p. 199.5-201 C., and4-diethylamino-6-(3-ethoxy-4- methoxypheny])pyrimidine, m.p. 2l8-219 C.

EXAMPLE XII Following the experimental details of Example I or III, andstarting with the appropriately substituted reagents, the followingcompounds are prepared:

EXAMPLE XIII 4-Diethylamino-6-(p-hydroxyphenyl)pyrimidine hydrobromide Asolution of 18.6 g. (0.1 mole) of 4-diethylamino-6-(p-methoxyphenyl)pyrimidine in 30 ml. of 48% hydrobromic acid and 30 ml.of glacial acetic acid is heated to the reflux temperature and gaseoushydrogen bromide slowly introduced below the surface during the firsttwo hours of refluxing. Heating is continued until thin layerchromatography indicates the reaction is complete. The reaction iscooled and the excess acetic acid and hydrobromic acid are removed underreduced pressure. The residual product is triturated with acetone,filtered and recrystallized from ethanol/hexane.

EXAMPLE XIV Following the procedure of Example XIII and starting withthe 6-(methoxyphenyl)pyrimidines of Example XII and the appropriatereagents the following analogs are prepared:

EXAMPLE XV The method of Example III is repeated, using the requisitestarting reagents, to provide the following congeners in moderateyields:

EXAMPLE XVI X 2 4-Diethylamino-6-(m-nitrophenyl)pyrimidine 2-NO H H Z-NOCH, H hydrochloride CZH To a solution of 1.0 g. (3.8 m moles) of 4- 5gig g i i diethylamino-6-phenylpyrimidine hydrochloride in 4-NO: H a 7 HJ ml. of concentrated sulfuric acid is added 10 ml. of nig-gg E tricacid dropwise at room temperature. The reaction Z Z HOUCHUF mixture isallowed to stir for 6 hours, and 18 then 2 HO(CH2)'1 Q)Z 4-NO2 nC H 3 1poured onto ice and made basic with concentrated am- 10 moniumhydroxide. The product is extracted into chloroform, and the organiclayer dried over sodium sulfate and concentrated in vacuo to an oil. Theresidual oil is EXAMPLE XiX dissolved in ethyl acetate and hydrogenchloride slowly 4-Diethylamino-6-( m-aminophehyl )pyrimidine introducedinto the solution until the precipitation is dihydrochloride complete.The hydrogen chloride salt 18 filtered, dried and recrystallized Asolution of 24.5 g. (0.8 mole) of 4-diethylamino-6- Anal. Calcd. for C Ho N HCl: c, 54.5; H, 5.6; N, p y )-Py hydrochloride, 62 Of 18.2 stannouschloride and 370 ml. of 12 N hydrochloric Found; C, 54.1; H, 5 N, 1 0 20acid contained in a 2 l. 3-necked flask is heated and stirred for 3hours at 60 C. and then allowed to stir at EXAMPLE XVII room temperatureovernight. The precipitate is fil- The nitration procedure of ExampleXVl is repeated, tered, washed with 12 N hydrochloric acid and disusingthe appropriate starting reagents, to provide the solved in water. Theaqueous solution is made basic following analogs in good yields: with10% sodium hydroxide solution and extracted with chloroform. Separationof the organic layer fol- 2 lowed by drying over sodium sulfate andconcentration to dryness provides the crude product as an oil. Theresidue is redissolved in chloroform and treated with 0 3O gaseoushydrogen chloride until a precipitate no longer forms. The product isfiltered and dried, 19.1 g., m.p.

w Mol wt.: Calcd. for 315.25. Found: 311

Equiv. wt.: Calcd. for 157.62. Found: 161

The free base, generated by treating an aqueous solution of thehydrochloride salt with a 10% sodium hydroxide solution, has a meltingpoint of 78 C.

R, R2 R; R R2 a H CZHS H CFJCHZ H H H iC H H CFSCHZ CZHS H H r1-C, H H H(CH3)ZN(CH2)2 H CH CH H CH HO(CHZ)2- H CH nC H l-l C 11,, Ho(cH H C Hn-C H H CH3 cyclo CGHH H nC H nC H-, H HO(CH2)2 cyclo C3H5 H -(CH2)4 HHO(CH2)2 HO(CH2)2 H (cH H CH =CHCH CH =CHCH, H (CH H H Z-HO CC H, H (CHO(CH H H 2-H NSO C H H H CH3 cyclo C3H-, CH3 2)2 a)( 2)2-* C H c H CH CHcyclo 0 H, C H iC H iC;,H CH CHZ=CHCH2 cyclo CGHH CH-J CH; CH; CZHSCEHE, CH5 CQHQ CH CH nC H EXAMPLE XVIII Anal. Calcd. for C,.,H,8N4; C,69.4; H. 7.5; N, 23.1. The procedure of Example 11 is repeated, startingFound: with the appropriate benzothienol3,2-dlpyrimidine, to provide inmoderate yields the following compounds: EXAMPLE XX The procedure ofExample XIX is repeated, starting with the compounds of Examples XVlland XVlil, to synthesize the following congeners:

9 of i 25 ml. of acetic anhydride. The resulting solution is SubstmmonR1 R2 R3 stirred overnight at room temperature and 1s then di- 2 H H Hluted with 500 m1. of ethyl acetate and treated with sufg fic1entgaseous hydrogen chloride to complete the pre- 2 2: =)i- H 5 clpltationof the desired product. The solvent and exa 1 $235 cess acetic anhydrideare removed under reduced pres- 3 H j H sure and the residue washed fromthe flask with 20 ml. 3 H nC H H of 1:1 hexane/ethyl acetate 6.6 g.,m.p. 235237 C. 3 E3 5: CZHS It proves to be identical to that preparedby the Acid :1 :s a 1 3 CH3 H 10 Chloride Method. 3 C 11 n C.H H 3l'l--C H n-C H H 3 a 1 (CH2)4LD H EXAMPLE XXII 3 z)5 H 3 H Startlng withthe suitably substltuted 6- 3 c H Z)Z g H I 5 aminophenylpyrimidine andrequisite reagents and folg 2 Z H 2 lowing the appropriate proceduremethod in Example 3 CF CH H H XXI the following compounds are prepared:3 CF CH C,H, H 3 H a)2 2 2 H 3 CH3 HO(CH2)2 H 3 CH cyclo C.,H C 111 3C211,, HO(CH H 3 cyclo C H HO(CH H 3 HO(CH)2 HO(CH2)2 H 3 CH =CHCH,CH,=CHCH H X 3 H 2HO2CC.,H4 H 3 H z-Huvso c H H 4 H H H 4 cH cH H 4 C HH H 4 C2H5 H0(CH,),- H 4 H0(CH,),- H0(CH,) H 4 nC H-, n C3H1 H Method xR, R, R m. C.

Anh dridc 3-NHc0CH nC H nC H H 128-129 Anhydride 3-NHC0CH -(CH H 289-29lAnh dride 3-t-lHC0CH n--C.H nC H H 193-195 Acid Chloride 3-NHC0C H C11,, C,H H 232-234 Acid Chloride 3-NHC0(CH CH C 11 C H H 215-2l8 AcidChloride 3-NH(:0CH(CH C H C H H 248-250 Acid Chloride 3-NHC0CF C 11 0 HH 149-151 Acid Chloride 3-NHCOC H C H c H H 230-234 Acid Chloride3-NHc0,cH C2115 C H H 223 dec. Acid Chloride 3-NHCO2C2H5 C,H C 11,, H224 dec. Acid Chloride 3-NHS0 CH C,H (3 H H 225 Acid Chloride 3-NHSO CHn-C H, n-C,H H 205 Anhydride 4-NHCOCH, C,H C,H,, H 272-275 dec.Anhydride 3-NHC0CH CH CH C,H 215-217 Anhydride B-NHCOCH C H c H CH174-176 Anhydride 3-NHC0CH C H (2 H, C,H 136-l38 Anhydride 3-NHCOCH nC HnC H CH 198-202 Anhydride B-NHCOCH; C 1 1, CH5 nC;,H 173475 EXAMPLE XXI4-Diethylamino-6-(m-acetylaminophenyl)pyrimidine hydrochloride AcidChloride Method To a suspension of 2.3 g. of sodium carbonate in 140 m1.of ether containing 5.1 g. (0.021 mole) of 4-Diethylamino-6-(m-aminophenyl)pyrimidine is slowly added 1.6 g. ofacetyl chloride in 20 ml. of the same solvent. The reaction mixture isstirred for 24 hours and is then treated with water. The ether layer isseparated, dried over sodium sulfate and concentrated in vacuo to anoil, which is taken up in ethyl acetate and treated with gaseoushydrogen chloride until a precipitate no longer forms. The product isfiltered and recrystallized from ethyl acetate/methanol, 2.1 g., m.p.236238 C.

Anal. Calcd. for C H ON .HCl: C. 54.5; H, 5.6; N. 17.9. Found: C, 54.1;H, 5.6; N 18.0.

Anhydride Method EXAMPLE XXIII The procedure of Example XXI is repeated,using the Method X R R R Anhydride 2-NHC0CH C H C l-l H Anh dridc2-NHCOCH C H n-C H H Anhydrlde 2-NHCO(CH CH;, C H nC3H1 H Anhydride2-NHCOCH(CH Cz 5 C2H5 H Acid Chloride 2-NHSO CH C,l-l C H H AcidChloride 3-NHSO C H, CH CH C2H5 Acid Chloride 3-NHCOCH CH CHZ)S HAnhydride 3-NHC0CH, H 2HO,CC6H H Anhydride 3-NHC0CH H 2H NSO C H, HAnhydride 4-NHCOCH, CH3 CH H Anhydride 4-NHCOCH,CH3 CH CH3 H AcidChloride 4-NHCOCH(CH CH CH H Anhydride 4-NHCOCH nC;,H-, nC H H Anhydride4-NHCHO nC H nC H-, H Acid Chloride 4-NHSO CH CH CH H Acid Chloridc4-NHCO2C2H5 CH, CH H Acid Chloride 4 NHC0CH5 n C,H, nC H H Anhydride3-NHC0CH CZHS CZHS C H Anhydride 3-NHCOCH CH, CH C,H

EXAMPLE XXIV -Continued 4-Diethylamino-6-(m-dimethylaminophenyl)pyrimi-X 2 3 dine hydrochloride CF CH H H To a solution of 2.6 g. (9.3 m moles)of 4- i'zzi f 2: 85 S r I I ll dlethylamino-6-(m-amlnophenyl)pyr1m1dmehydro- 4 N(CH:): C I-i HO(CH H chloride in 50 ml. of water is added 4.72g. of sodium $2253 E a- E carbonate followed by the slow add tion of2.74 g. of 2 CH3 H methyl iodide. The reaction mixture 15 heated to there- 4' z 5)2 z s HO(CH2)2 H 4-N(n-C;,H CZHE, HO(CH)2 H flux temperaturefor 6 hours, and is then cooled and ex- 4 N(n CaH7)2 n C3H7 n CaH7 Htracted with chloroform. The organic layer is separated, dried oversodium sulfate and evaporated in vacuo to a light brown oil.Chromatographing on a silica gel column and eluting with ethyl acetateprovides the desired product as a light yellow oil which when dissolvedin ethyl acetate and treated with gaseous hydrogen chloride provides thecorresponding crude hydrochloride salt. Further purification is effectedby recrystallization from methanol/ethyl acetate, 0.9 g., m.p. 170-l73C.

EXAMPLE XXV Following the procedure of Example XXIV, and starting withthe requisite 6-aminophenylpyrimidine and appropriate reagents, thefollowing compounds are synthesized:

EXAMPLE XXVI Starting with 2-bromothiophene and the requisite reagents,and following the procedure of Example I, the following congeners areprepared:

EXAMPLE XXVII 4-Diethylamino-6-( 5-actylamino-2-thienyl )pyrimidinehydrochloride A mixture of 28.26 g. (0.09 mole) of 4-diethylamino-6-(5-nitro-2-thienyl) pyrimidine hydrochloride and 35 g. of granular tinis treated, portion-wise, with 75 ml. of concentrated hydrochloric acid.Cooling is necessary once the reaction has started. When the reactionhas subsided, the clear hot solution is decanted from the unreacted tinand cooled in a salt-ice bath, and the resulting aminehydrochloride-stannic chloride complex which precipitates is filtered.

The complex is added to 75 ml. of water and 80 ml. of diethyl ether, andtreated with sufficient sodium hy' droxide to provide a pH of 9-10. Theether layer is separated, treated wtih 14.8 g. (0.135 mole) of aceticanhydride and heated to reflux for 3 hours. The resulting solution iswashed with sodium hydroxide solution, separated, dried over sodiumsulfate and concentrated to dryness. The product is dissolved in ethylacetate and sufficient hydrogen chloride gas bubbled into the solutionto precipitate the product as the hydrochloride salt. Recrystallizationfrom isopropanol provides the pure product.

EXAMPLE XXVlll Employing the procedure of Example XXVII, the startingwith the appropriate reagents, the following compounds are synthesized:

Position of RCONH EXAMPLE XXIX The procedure of Example 111 is repeated,starting with the appropriate reagents, to provide the followingcongeners in good yields:

Ill 5 I if N 5 0 t W R ON EXAMPLE XXX The procedure of Example III isagain repeated, using the requisite starting reagents, to provide, ingood yields, the following products:

Ar N W O N 3 N R R Ar R, R R

l-naphthyl C H C H H l-naphthyl n-C,-,H C H H l-naphthyl CF CH C H Hl-naphthyl CF CH C H C,H l-naphthyl HO(CH C H H 2-naphthyl H H2-naphthyl cn-i cm, c n, Z-naphthyl n-QH nC:,H H Z-naphthyl (CH N(CH H H2-naphthyl C H CF CH H 2-naphthyl (CH N(C H (CH H Z-naphthyl HO CC H, HZ-indolyl CH H H Z-indolyl CH CH H Z-indolyl CH CH CH 2-indolyl C H CFCH H 2-indolyl CH =CHCH C H H 2-indolyl HO(CH C H CH 2-indolyl HO(CH C HH Z-indolyl iC H iC H, H 3-indolyl CH CH H 3-indolyl --(CH O(CH- H3-indolyl C H C H H 3-indolyl H HO CC H H 3-indolyl H H NSO C H H3-indolyl H H NSO C H C 13 Z-benzofuryl CH C H H 2-benzofuryl HO(CH C HH Z-benzofuryl CF CH C H H 2-benzofuryl CF CH C H nC H 2 benzofuryl (CH),N(CH C H H Z-benzofuryl -(CH H 3-benz0furyl CH CH, H 3-benzofuryl C Hcyclo C 11 H 3-benzofuryl C H C H 5 H 3-benzofuryl C H CgH iC H-,3-benzofuryl -(CH ),S(CH H 3-benzofuryl i-C H, iC H, H 3-benzofuryl CH;cyclo C H H EXAMPLE XXXI The procedure of Example i is repeated,starting with the appropriate 2- or 3-halobenzo[b]thiophene andrequisite reagents, to provide the following compounds in moderatelygood yields:

Ar N W N R 3 N R R Al R1 R:

2-benzothienyl CH H H Z-benzothienyl C,H CH H 2-benzothienyl C H CH CH2-benzothienyl C H cr cu H 2-benzothienyl CH cyclo C5Hg H Z-benzothienylCH cyclo C.;H H 3-benzothienyl CH CH H 3-benzothienyl CH CH C H3-benzothienyl C H HO(CH H 3-benzothienyl C H CF CH H 3-benzothienyl HHO CC H, H 3-benzothienyl H H NSO C H H 3-benzothienyl H (CH N(CH l 3 H3-benzothienyl CH =CHCH CH =CHCH H EXAMPLE XXXII4-Diethylamino-6-(S-acetylamino-Z-furyl)pyrimidine hydrochloride To amixture of 2.62 g. (0.01 mole) of 4-diethylamino-6-(5-nitro-2-furyl)pyrimidine and aluminum amalgam,prepared from 4.0 g. of aluminum turnings, in 60 ml. of diethyl ether isadded 4 ml. of water. Acetic anhydride (2.0 g.; 0.02 mole) is addeddropwise during the ensuing reaction which is maintained by heating thereaction vessel in a warm water bath. The ether is filtered and thefiltrate dried over sodium sulfate. Removal of the solvent under reducedpressure provides the crude product. The residue is dissolved in ethylacetate and treated with gaseous hydrogen chloride until a precipitateno longer forms. The resulting hydrochloride salt is further purified byseveral recrystallizations from methanol/hexane.

EXAMPLE XXXlII The reduction-acylation procedure of Example XXXII isrepeated, using the appropriately substituted starting materials, toprovide the following analogs:

EXAMPLE XXXIV The procedures of Examples XIX and XXI are repeated, usingthe requisite starting reagents, to provide the following compounds inmoderate yields:

RCONH Position of Substitution EXAMPLE XXXv4-Diethylamino-6-(2-furyl)pyrimidine hydrochloride Crude4-diethylamino-6-(2-furyl)pyrimidine (3.2 g.;

0.015 mole), obtained by repeating the procedures of 5 EXAMPLE XXXvll1-[ 3-( 6-Diethylamino-4-pyrimidinyl)phenyl]-3- phenylurea hydrochlorideTo 2.6 g. (0.01 I mole) of 4-diethylamino-6-(maminophenyl)pyrimidine in40 ml. of ether is added dropwise 1.3 g. of phenylisocyanate dissolvedin 40 ml. of the same solvent, and the resulting mixture allowed to stirovernight at room temperature. Removal of the solvent under reducedpressure provides the crude product, 3,4 g., which is recrystallizedfrom ethyl acetate/methanol, 2.3 g., m.p. 183l84 C.

phase is dried over sodium sulfate and treated with sufficient gaseoushydrogen chloride to completely pre- Anal, calcd, f CZIHzaONs; @693;11,64, cipitate the hydrochloride salt, which is filtered, wash- Found:9. H. 6 5; N. 19.6 ed with acetone and dried, m.p. l79-l80 C.

EXAMPLE XXXvl EXAMPLE XXXVIII Starting with the appropriatelysubstituted reagents The procedure of Example XXXVII is repeated, andemploying the respective procedures indicated, the using the appropriatestarting regents, to provide the following products are synthesized: f ni analogs in good yields;

N Y-NH N R XI 2 R1 R R; R Procedure 3-CH3CO H CH3 CH3 H H Example Ill3-CH -,CO H C H C H. H H Example lll 3-CH3CO H (CHe)e H H Example Ill4-CH CO H CF CH, C,H, CH H Exam le lll 4-CH3CO H HO(CH2)2-- CgHg CH3 HExample Ill 4-cH,co H H Ho cc H CH3 H Exam le lll 4-cH co H -(CH,).- CHH Exam le lll 3|4'CH2O2 CgH5 C1H5 H H Example I 3,4-GHQ, Ho(cH,),- C,H HH Exam le 1 3,4-CH 0 clcH H H H Exam le l 3.4-cH,o, CH,=CHCH C,H5 H HExample 1 3-NO, 4-Cl CZHI, CgH5 H H Example XVI 3-NO2 4-Cl CFQCHZ CH5 HH Example XVI s-No, 4-0CH CF CH, C2H5 H H Exam le XVI B-NO, 4-OCH C HCgH H H Example XVI 3-N0, 4-F -(CH H H Example xvl I l-NH, 4-Cl C,H, 6H, H H Example Xlx S-NH, 4-Cl CF CH C,H, H H Exam le xlx 3-NH, 4-OCH3CFgCHg C H H H Example XIX s-NH 4-ocH 02H. C H H H Exam le xlX 3-NH 4-FH H H Exam le XIX B-CH CONH 4-Cl c,H c,,H5 H H Example xxl 3-CH3C0NH 4Cl cFacH, C H H H Exam le XXI B-CHQCONH 4-OCH3 CF3CH C2H5 H H ExampleXXI B-CH CONH 4-ocH C,H 0 H, H H Example XXI 3-CH -,CONH 4-F -(CH,).-, HH Exam le xxl 3-CH;,O CNH 4-Cl c,H5 (3 H, H H Exam le xxl 3-C2H,O2CNH4-OCH C=H CgHf, H H Example XXI 3-C,,H,0,CNH 4-F -(CH,). H H Exam le XXIs-cH coNH H c,H H,, CH cH Example I 3-CH CONH H CZH, CF CH CH, CH Examle I 3-CH CONH H c H, C H H C,H, Example I 3-(CH;)2NC0 H CZHS C,H5 H HExample XXI 3- C,H,,)Nc0 H c H, C H H H Example XXI EXAMPLE XXXlXTablets A tablet base is prepared by blending the following ingredientsin the proportion by weight indicated:

Sucrose. U.S.P. 80.3 Tapioca starch 13.2 Magnesium stearate 6.5

Into this tablet base there is blended sufficient 4-diethylamino-6-(m-acetylaminophenyl)pyrimidine hydrochloride to providetablets containing 20, 100 and 250 mg. of active ingredient per tablet.The compositions are each compressed into tablets, each weighing 360mg., by conventional means.

EXAMPLE XL Capsules A blend is prepared containing the followingingredients:

Calcium carbonate, U.S.P. 17.6 Dicalcium phosphate 18.8 Magnesiumtrisilicate, U.S.P. 5.2 Lactose, U.S.P. 5.2 Potato starch 5.2 Magnesiumstearate A 0.8 Magnesium stearate B 0.35

To this blend is added sufficient 4-diethylamino-6- EXAMPLE XLllSuspension A suspension of4-diethylamino-6(m-propionylaminophenyl)pyrimidine is prepared with thefollowing composition:

Effective ingredient 25.00 g. 70% Aqueous sorbitol 741.29 g. Glycerine,U.S.P. 18535 g. Gum acacia (10% solution) 100.00 ml.Polyvinylpyrrolidone 0.50 g.

Distilled water Sufficient to make 1 liter To this suspension, varioussweeteners and flavorants are added to improve the palatability of thesuspension. The suspension contains approximately mg. of effective agentper milliliter.

25 EXAMPLE XLlll Solution A solution of4-diethylamino-6-(p-methoxyphenyl)- pyrimidine hydrochloride is preparedwith the following composition:

Effective ingredient 30.22 grams Magnesium chloride hexahydrate 12.36grams Monoethanolamine 8.85 ml. Propylene glycol 376.00 grams Water,distilled 94.00 ml.

The resultant solution has a concentration of effective ingredient of 50mg./ml. and is suitable for parenteral and especially for intramuscularadministration.

EXAMPLE XLlV Starting with the appropriately substituted 4-chloro-6-arylpyrimidine and requisite piperazine and repeating the procedure ofExample l-D, the following ana' logs are prepared in good yields:

Ar N (m-dimethylammophenyl)pyrimidme hydrochloride to provide capsulescontaining 20, 100 and 250 mg. of ac- 0 tive ingredient per capsule. Thecompositions are filled N into conventional hard gelatin capsules in theamount of 350 mg. per capsule.

EXAMPLE XLI lnjectable Preparation One thousand grams of4-diethylamino-6- N phenylpyrimidine hydrochloride are intimately mixedl and ground with 2500 grams of sodium ascorbate. The ground dry mixtureis placed in vials and sterilized with O X Ar X Ar X Ca-i CH 4 FC H,OCH(CH;,)2 C l-i CH(CH,) 4FCGH,, CH CSH5 OCHE 4-FC,-,H, 2furyl 4-ClC H Cl-l 3BrC H 2 -furyl 4-CIC H OC H 3-BrC H C 14 4ClC H cn-t 3-BrC H,OCH2C(CH3)=H, 4-OCH C H, OCH C H 3N(CH1)2CGH4 ()CH,C(CH,)=CH 4'OCH3CGH,CH3 3-N CH, C,H, 2furyl EXAMPLE XLV In Vitro Inhibition of PlatletAggregation The ability of the compounds of the present invenlowed bythe addition of compounds of the present invention at levels of 6 X 10",10' and moles/liter. After 10 minutes of incubation with theplatelet-rich plasma at room temperature, collagen, a protein known tocause platelet aggregation, is added (0.27 ml. collagen/4 ml. plasma)and changes in the optical density are followed with a Spectronic 2Ocolorimeter attached to a Houston Instrument TY Recorder. Plateletaggregation is indicated by a decrease in optical density. The relativepotency of the compounds of the present invention are thus rated ontheir ability to inhibit (percent) collagen induced plateletaggregation.

The following compounds were evaluated:

tion inhibit platelet aggregation in vitro is measured ac- N cording tothe method of Born, et al., J. Phys1ol., 168, Ar

178 (1963) and comprises the following procedure:

Anesthetized male rabbits are bled from a carotid ar- N tery intoplastic centrifuge tubes containing 0.1 volume R 3% sodium citrate.Platelet-rich plasma is separated by 3 centrifugation at G for 10minutes at 20 C. Plasma N from 3 animals is pooled; 5 ml. samples areplaced 1nto clear plastic curvettes and stirred at 1000 rpm, fol- 1 2Inhibition Concentration moL/l. Ar R, R R 6 x 10- 6 x 10" 6 X 10*

1. A COMPOUND SELECTED FROM THOSE OF THE FORMULA 2.4-Hydroxy-5-ethyl-6-phenylpyrimidine.